Introduction Vascular dysfunction is a hallmark of chronic kidney disease (CKD), with previous studies showing progressively deteriorating microvascular reactivity in skeletal muscles with advancing CKD stages. Additionally, cognitive impairment is quite common in CKD patients, as significant determinants of brain activation, i.e., cerebral perfusion and oxygenation, are significantly impaired. The aim of this analysis was to investigate, for the first time, the effects of proteinuria on skeletal muscle and cerebral oxygenation, as well as on muscle microvascular reactivity in patients with pre-dialysis CKD. Methods A total of 56 patients with pre-dialysis CKD were included in this post-hoc, exploratory analysis and stratified based on the presence of proteinuria (urinary protein-to-creatinine ratio textgreater 200 mg/g). Patients with and without proteinuria were matched in a 1:1 ratio for age, sex, and estimated glomerular filtration rate (eGFR). Near-infrared spectroscopy was used to measure muscle and cerebral oxygenation at rest and after stimulation (occlusion-reperfusion and handgrip exercise). Results The two groups were similar in terms of age, eGFR, body mass index, and major comorbidities. Muscle oxygenation did not differ between study groups at rest and during occlusion; however, proteinuric CKD patients presented a trend toward lower tissue saturation index (TSI) during reperfusion (10-second slope: 1.36±0.69 vs. 1.67±0.83, p=0.143) and hyperemic response (7.26±3.98 vs. 8.47±4.52, p=0.296). Regarding cerebral oxygenation, proteinuric patients displayed lower average response during exercise (oxygenated hemoglobin [O2Hb]: 0.92±0.78 vs. 1.49±0.86, p=0.012; hemoglobin difference [Hbdiff]: 1.41±0.96 vs. 1.98±1.12; p=0.044). The average response in total hemoglobin (tHb) (an index of regional blood volume) was also lower (0.43±0.98 vs. 1.00±0.85, p=0.023), but no between-group differences in deoxygenated hemoglobin (HHb) (an index of oxygen extraction capacity) were observed. Conclusions In this exploratory analysis, CKD patients with proteinuria showed signs of attenuated cerebral oxygenation during a mild physical task and a possible trend toward modest impairments in skeletal muscle oxidative capacity and microvascular reactivity.